Strategies for Engineered Negligible Senescence

Strategies for Engineered Negligible Senescence or SENS is a proposal by Aubrey de Grey to cure aging. SENS has gathered widespread media and public attention, yet it has also been vehemently attacked by a number of experts. This essay briefly presents SENS and the arguments from both sides on its merits and drawbacks.

About 10 years ago, Aubrey de Grey proposed the SENS approach with the goal of curing aging (de Grey et al., 2002a; de Grey, 2003; de Grey and Rae, 2008). Briefly, his proposal is that even if we do not know the underlying mechanisms of aging, if we can engineer the reversal of all the major molecular and cellular changes that occur with age, we will be able to reverse aging and rejuvenate ourselves. The proposal includes addressing seven forms of molecular or cellular damage, based on earlier works (Holliday, 1995), that accumulate with age:

Cell loss, tissue atrophy

Nuclear [epi]mutations (only cancer matters)

Mutant mitochondria

Death-resistant cells

Tissue stiffening

Extracellular aggregates

Intracellular aggregates

de Grey then proposes a number of creative solutions to reverse the above forms of damage. The solutions, however, are based on technologies and therapies that are not yet available or at least not yet developed to do what is necessary for SENS. These include stem cells to replace old cells, the application of enzymes--including bacterial enzymes--to degrade certain forms of cellular junk, gene therapy technologies that allow the incorporation of transgenes with a high efficiency and viability, and the ablation of old cells.

The idea that curing aging may be possible before we can fully answer the main issues in the field is original but controversial. de Grey assumes we can understand the changes that occur with age well enough to develop therapies, even if the causality of these is not yet established. Like previously discussed, many pharmaceutical interventions work as intended even though we do not know why. Some anti-aging therapies may follow the same principle: for instance, maybe we do not need to know the exact functions a given gene shown to retard aging in model systems to develop anti-aging drugs by targeting that gene, as discussed earlier. Likewise, perhaps we do not need to know the mechanisms leading to damage in order to repair it to preserve health. SENS, however, promises radical results: a cure for aging within a relatively short time of a couple of decades. Even though it is plausible that if the technologies in which SENS is based on--e.g., stem cells, tissue engineering, and gene therapy--reach a high level of sophistication then anti-aging research will greatly benefit, the idea that we can cure a complex process like aging without knowing its underlying mechanisms is, of course, debatable and SENS has been criticized by numerous scientists (Warner et al., 2005; Warner, 2006; Holliday, 2009).

One key criticism of SENS comes from analogies with other medical problems like cancer. Since US President Nixon declared the war on cancer in 1971, the R&D spending on cancer has been estimated at $100-$300 billion. Some new treatments have been developed but while overall cancer survival has increased in recent decades this is mostly due to early detection rather some "magic bullet" (Lakdawalla et al., 2010). From a engineer's perspective, however, cancer is a simple problem: all we need to do to cure it is the ablation of cancer cells. This is similar to the ablation of death-resistant cells in the SENS proposal. In the case of SENS, de Grey proposes that ablation of cells may be achieved by making unwanted cells commit suicide or stimulating the immune system to kill them. The issue then is: if the ablation of unwanted cells were so simple, then why have decades of cancer research, with way more money than is available to aging research, failed to do so? Essentially the problem is that developing therapies that destroy harmful cells but not normal cells is technically very challenging and has not been solved yet in spite of a massive investment and research effort. As a side note, de Grey's proposal to target cancer actually involves restricting telomere elongation in the whole body by deleting the genes responsible and then, because telomere elongation is necessary for self-renewal in some tissues, use cell therapy and tissue engineering to keep organs healthy (de Grey, 2005b).

It can be argued that we still do not have the necessary technologies to implement SENS or cure cancer but are now on the verge of developing them. On the other hand, critics of SENS point out that these engineering achievements are actually very difficult to achieve due to intrinsic problems and limitations of of biomedical research. There are still few success stories of engineering in biology, even in lower organisms, in part due to our incomplete knowledge of biological systems (Heinemann and Panke, 2006). As such, critics of SENS argue that all individual components of the SENS proposal are exceptionally optimistic (Warner et al., 2005; Holliday, 2009). A related issue is that interventions in medicine, including stem cell therapies and others that are essential for SENS, are intrinsically difficult to develop and perfect. As mentioned elsewhere, the rate of success of drugs in clinical trials is only 20% (DiMasi et al., 2010), which is due to the intrinsic complexity and unpredictability of biological systems. As such, critics of SENS argue that the chances that each SENS component will be successful are actually very low and the SENS agenda, to quote a group of gerontologists who criticized it, "is so far from plausible that it commands no respect at all within the informed scientific community" (Warner et al., 2005). Indeed, as Warner et al. point out, none of de Grey's proposals to tackle the seven forms of damage has been shown to extend lifespan even in simple model organisms. The relevance of these seven types of damage to aging is far from proven and other processes that are not tackled in SENS may prove important to aging (Warner, 2006). de Grey responded to the above criticisms (de Grey, 2005c & 2006). Briefly, he argues that the effects of tackling the seven forms of damage can only be correctly evaluated when tested together rather than individually. de Grey also argues that Warner et al. are being pessimistic about progress of technology and that indeed relevant technologies for SENS are forthcoming. A final point is that even before curing aging we may reach a stage, which de Grey calls "anti-aging escape velocity," where successive medical advances postpone aging faster than time is passing (de Grey et al., 2002b).

Even though SENS is controversial and polarizing, it can be argued it has had positive effects in the field by fostering discussion of key issues and, given that de Grey is arguably the most famous gerontologist in the world, raising awareness to research on aging and life-extension. de Grey's advocacy and optimistic vision is no doubt important to attract and excite young scientists and students to study aging and try to develop interventions to extend human lifespan. The public interest generated by SENS can be argued to even influence funding policy and thus have a positive influence for the field (de Grey, 2005d). Projects originating in SENS, such as the Mprize for longevity or rejuvenation breakthroughs in mice, also foster development of life-extension therapies. The SENS foundation also provides funding for a number of high-risk, high-reward technologies and approaches. Critics of SENS, however, point out that numerous false anti-aging claims throughout the centuries have given the field a poor reputation and that SENS will further erode the public's confidence in gerontology; the attention given to the SENS agenda may also divert resources for what they think are more promising research foci (Warner et al., 2005). Because of its controversial nature, however, SENS does not--at the time of writing--receive funding from traditional funding bodies, such as government agencies and charities, and so it is unclear if indeed SENS is diverting funds from other researchers or instead generating new sources of funding (e.g., private donations) that would normally not be available to traditional gerontologists.

August Weismann wrote: "The complex processes of life can only be followed by degrees, and we can only hope to solve the great problem by attacking it from all sides." In a field like gerontology where proven facts are rare, it is important to invest a certain amount of resources in unorthodox practical research; reasonable ideas that go against some of the most popular theories can also be successful and History proves it. When Einstein thought and developed his ideas trying to solve the paradoxes relating light speed and confronting Newton's and Maxwell's laws, he was unaware that others were thinking about the same problems; this was a blessing, for the others were heading in wrong directions and could have clouded his thoughts. Therefore, large advances in science and technology are often due to individuals following what others think is an impossible vision and investing some aging research funds in risky ideas is clearly important (Strehler, 1986). Even if the components of SENS are regarded by many--possibly most--scientists as optimistic and by some even as unrealistic, positive outcomes may emerge from developing such approaches, even if falling short of curing aging.

I discussed above--hopefully in a balanced and objective way--the different arguments, strengths and weaknesses regarding SENS and hopefully readers can now make up their own decisions about it or dig deeper into the cited references and the links below. Still, it would be cowardly of me not to explicitly mention my personal opinion on this issue, and many have asked me about it, so I will make it clear. I have no doubt that SENS is highly optimistic. Part of the problem is that SENS, like the proposals of futurist Ray Kurzweil (Kurzweil and Grossman, 2004; Grossman, 2005), depends on technologies that have not been developed yet and thus may or may not pan out. The unpredictability of biological systems, in particular, is a key issue to render SENS very optimistic in my eyes. I personally think that a much deeper understanding of biology, and specifically of the machines of life, is essential to develop the level of sophistication in biomedical research (including pharmacology, synthetic biology and regenerative medicine) required for curing aging. Hence, the focus of my work is not on SENS but on increasing our knowledge of aging and on genomics, as discussed elsewhere. I also think a better understanding of the mechanisms of aging is important to develop more specific therapies--the types of damage in SENS are quite broad--that will have a higher chance of success. On the other hand, and unlike many gerontologists, I aim to cure aging, and not surprisingly I disagree with the many SENS critics who reject any possibility to prevent aging indefinitely or reverse aging (Warner et al., 2005). It may be extraordinarily hard to cure aging, but there is no scientific reason to think it is impossible, as I discuss elsewhere. de Grey has, in fact, tackled one of the major issues in getting more attention and funding to anti-aging research: he attacked the view that aging is untreatable. Since I have no doubt that increasing public understanding and support is of prime importance for us to cure aging, the SENS initiative has, in my opinion, been very positive because of the momentum it generates, of how it raises awareness and rallies the field. Probably SENS will not cure aging but it may create the opportunities for others to cure it.